Acetaminophen and NSAIDs have been used routinely for treatment of pain and/or fever. This dual action is sometimes contraindicated. In many instances, pain needs to be controlled without masking symptomatic fever (e.g., during the postoperative period). These drugs can cause hepatotoxicity, particularly after ingestion of large doses or from chronic use (especially when liver function has been compromised), which can lead to death. We are exploring a series of new and proprietary derivatives of acetaminophen that have good pharmacological potency and little hepatotoxic, nephrotoxic, or antipyretic effects. In preliminary studies, the initial compounds demonstrated high analgesic activity free from antipyretic activity and hepatotoxicity. In Phase I, we further characterized these initial compounds and several other analogs/derivatives and identified a lead candidate drug. We will further test and develop this drug in Phase II for treating postoperative pain and for other analgesic treatments where acetaminophen is contraindicated. We will also use a combination of in vitro and in vivo models to evaluate additional analogs and derivatives of the Phase I lead candidate drug. We will choose second-generation candidates based on efficacy, pharmacokinetic, and toxicity evaluations. PROPOSED COMMERCIAL APPLICATION: The market for pain relievers in the US is estimated to be approaching $6 billion. Acetaminophen (marketed under the name Tylenol(TM) and other brand names) represents about 48% of that market. Although widely used, acetaminophen is not without some serious side effects. There is a clear unmet medical need for pain relievers that are effective but have a better safety profile than acetaminophen. This research is directed at developing a pain reliever that is as effective as acetaminophen but with fewer side effects. This drug would be targeted at those patients most at risk from acetaminophen toxicity, particularly those who must take pain relievers on a chronic basis, and those with postoperative pain where masking of fever by acetaminophen could delay the diagnosis of infection.